Blood lipids influence DNA methylation in circulating cells

Area of Science:

• Genomics
• Epigenetics
• Metabolic Disease

Background:

• Cells acquire long-term epigenetic memory from external stimuli.
• Elevated blood lipids may prime immune cells via DNA methylation, contributing to atherosclerosis.
• Investigating causal links between blood lipids and DNA methylation is crucial for understanding disease mechanisms.

Purpose of the Study:

• To determine the causal relationship between triglyceride, LDL cholesterol, and HDL cholesterol levels and genome-wide DNA methylation.
• To exclude confounding factors and pleiotropy in the lipid-DNA methylation association.
• To utilize Mendelian randomization for robust causal inference.

Main Methods:

• Stepwise Mendelian randomization analysis.
• Whole blood samples from 3296 individuals.
• Multivariable Mendelian randomization and RNA-sequencing data analysis.

Main Results:

• Differential DNA methylation is a consequence of blood lipid levels, not vice versa.
• Triglycerides affected DNA methylation at three CpGs, LDL cholesterol at one, and HDL cholesterol at two.
• CpG methylation changes correlated with key lipid metabolism gene expression (CPT1A, SREBF1, DHCR24, ABCG1).

Conclusions:

• Epigenetic priming plays a role in lipid metabolism feedback control.
• Mendelian randomization is effective for inferring causality in integrative genomics.
• Findings provide insights into the molecular mechanisms linking lipids and epigenetic modifications.